The present invention relates to a polymeric system, and more particularly to a system which releases drugs in response to environmental stimuli or separates solutes.
The human body has its own homeostatic mechanisms to regulate a variety of physiologic parameters within a certain range. These parameters include temperature, pH and salt content. In instances of disease, however, these parameters may be affected due to various mechanisms. It is essential that the body maintain homeostasis for proper conditions for enzyme reactions and metabolism to be carried.
In infection, the interactions between polymorphonuclear cells and bacteria may result in the production of pyrogens. These pyrogens may disrupt the thermo-regulatory system located in the hypothalamus of the mid-ventricle in the brain resulting in an elevation of the temperature threshold and the normal body temperature. (1) Also, in localized inflammation, the immune system of the body responds with an increase in vasodilation and release of many inflammatory mediators. Histamine, for example, results in an increase in vasodilation and consequently, the permeability of capillaries increases (2) with resulting edema. Sites of inflammation also manifest with an increase in temperature. Products of reactions resulting from inflammation are usually acidic. Therefore, the pH of the local area is reduced.(3)
In tumors, research has demonstrated that the intracellular region is of a lower pH than the extracellular region.(4) Hyperthermia has also been studied as an adjunct in cancer chemotherapy. It was found that tumor cells were more sensitized to chemotherapeutic agents when heat was applied locally to the tumor site.(5)
Regulated drug delivery, or more appropriately called, stimuli-responsive drug delivery, is a concept in which a drug or drugs is/are delivered at an appropriate rate in response to stimuli. As aforementioned, disease states may cause a change in some parameters of the body and this can be used as a stimuli or a xe2x80x9ctriggerxe2x80x9d for the onset and offset of the delivery of drugs. Certain polymers exhibit property changes in response to variations in temperature, and pH. A number of these polymers have been investigated extensively and some success in drug delivery with them has been achieved. For example, polymers loaded with glucose oxidase have been used for regulated delivery of insulin according to the amount of glucose in the body. The glucose reacts with glucose oxidase producing an acid which induce the swelling of the polymer thus increasing the release of insulin.(6) Thermosensitive polymers such as poly(N-isopropylacrylamide) (PNIPAm) have also been used for regulated drug delivery. Such polymers experience a dramatic change in hydration when the temperature is increased or decreased through the phase transition temperature (Ttr). At T less than Ttr, the polymers swell and release more drug; at T greater than Ttr, the polymers collapse resulting in a decrease in release rate due to the formation of dense skin following a pulsatile release at the initial stage.(7) However, in light of this, type of delivery system suffers from negative thermosensitivity, i.e., which is in the opposite direction of the slow of therapeutic agents associated with hyperthermia. In addition the system has the disadvantages of slow response and low mechanical strength.
To overcome these problems, several new designs of thermosensitive delivery systems have been developed.(8-13) These include a hydrogel-valve cylindrical device (14) and various membrane systems. Positive thermoresponse (i.e., higher release rate at higher temperature) has been obtained and mechanical strength has been improved in these systems. However, their application is limited by the methods of fabrication. For example, one is a cylindrical device with a hard plastic shell in which a drug solution is enclosed. The release of the drug solution is controlled by a piece of hydrogel which changes volume with temperature. Unfortunately, the volume change of the hydrogel is rather slow because of its size. Moreover, the device, with a rigid shape, requires surgery for introduction and removal from the body.
Existing membrane systems that exhibit positive thermosensitivity are prepared by chemical reactions such as cross-linking, grafting or radical polymerization.(8-13) Therefore, purification is required after the fabrication of the membrane. More importantly, and a clear disadvantage of such systems is that the reaction conditions are hazardous for therapeutic agents, especially those biological products such as proteins and peptides.
The human body is known to exhibit certain circadian rhythms according to different times of day. It has been found that for some anti-cancer agents, their toxicity can be minimized if the drug is administered at a certain time of the biological clock. Tumor cells are found to multiply at different rates during different time of the day. They are also known to follow a circadian rhythm. Clinical trials have demonstrated that therapeutic agents administered according to circadian rhythms are more effective and less toxic than the standard schedule of therapy.(15) Therefore, pulsatile delivery of drugs may be advantageous over the constant delivery.
With the development of recombinant DNA technology in the production of proteins and peptides, more and more new protein and peptide drugs are synthesized. In biotechnological processes such as fermentation, a number of peptides may be produced in one batch. These processes require further purification of the products.(16) Therefore, it is necessary to design a membrane that can separate a series of compounds of various molecular weights.
In vivo instability especially enzymatic degradation, hinders application of proteins and polypeptides as therapeutic agents. As such it is desirable to have a delivery system that can allow therapeutic agents to diffuse out while preventing the enzymes from entering.
This invention involves the development of a composite polymeric system containing stimuli-responsive particles and at least one other polymer. As used herein, the term xe2x80x9cparticlesxe2x80x9d includes nano- or microspheres, or any other particles having dimensions within the range from nanometeres to millimeteres. The system and particles can be of any shape. This new system can be made to be biocompatable and can be biodegradable. The system can change pore size quickly in response to external stimuli such as pH, temperature, ionic strength, multivalent ions, and other chemicals, i.e., it is stimuli-responsive and consequently it can provide stimuli-responsive drug release. Further, pore size of the system can be tailored for release and/or separation of solutes of different sizes. It can also protect protein and polypeptide drugs from enzymatic degradation.
Broadly stated, the present invention relates to a composite polymer system comprising stimuli-responsive particles, preferrably nano- or microspheres, and at least one other polymer. The xe2x80x9cat least one other polymerxe2x80x9d is referred to herein as a second polymer. Second polymer can be one or more other polymers, i.e., one, two three or more xe2x80x9csecond polymersxe2x80x9d. The invention provides a polymeric system which strengthens the mechanical strength of a responsive component using at least one other polymer, i.e., second polymer which acts as a matrix and to increase the response rate of the system. A responsive component such as PNIPAm/MAA nanoparticles act as responsive nanovalves which can form channels in response to changes in external stimuli like temperature and pH. This invention can potentially be applied to other systems comprising a swellable hydrogel and nonswellable hydrophobic polymer.
Accordingly, the present invention provides a composition for a composite polymer system comprising a stimuli-responsive polymer, preferrably swellable, and at least one second polymer, preferrably non-swellable and hydrophobic.
According to a preferred embodiment the stimuli-responsive polymer is selected from the group consisting of R-acrylamide, R1-acrylate, R2-acrylic acid, and polyethylene glycol where R, R1, and R2 may each be H or alkyl.
According to another preferred embodiment the second polymer is selected from the group consisting of polysaccharides, polysaccharide derivatives, cellulose, cellulose derivatives, polyesters; anhydrides; poly(orthoesters); and polyurethane. Most preferably a composition according to this invention is biocompatable and biodegradable. A preferred embodiment is a composite polymer system comprising poly(N-isopropylacrylamide-co-methacrylic acid) and ethylcellulose.
The invention also broadly contemplates methods for preparing composite polymeric systems of the present invention containing stimuli-responsive particles, preferrably nano- or microspheres, and at least one second polymer as follows:
(a) obtaining particles with suitable responsive properties and sizes;
(b) mixing the particles with at least one second polymer solution;
(c) casting the composite polymer system. The system can be case in any shape which is desired or appropriate depending upon the application.
Accordingly, the present invention provides a method of preparing composite polymer system, preferrably with particles that are nano or microspheres comprising: (a) preparing particles with a stimuli-responsive polymer; (b) adding and mixing at least one second polymer, preferrably non-swellable and hydrophobic, under conditions which permit dispersion of the particles in the second polymer; and (c) casting the resulting composite polymer system.
According to a preferred method the stimuli-responsive polymer is selected from the group consisting of R-acrylamide, R1-acrylate, R2-acrylic acid, and polyethylene glycol where R, R1, and R2 may each be H or alkyl.
According to a further preferred method the second polymer is selected from the group consisting of polysaccharides, polysaccharide derivatives, cellulose, cellulose derivatives, polyesters; anhydrides; poly(orthoesters); and polyurethane.
According to preferred embodiments the step of mixing is carried out by melting the polymers or mixing them in solution.
The composite polymeric systems of the present invention may also be used in any one or more of the following applications: solute separation and filtration; temperature, pH and ionic strength and biochemical ionsxe2x80x94responsive drug delivery; diagnostic and monitoring tools; protein and peptide drug delivery; and coating and microencapsulation of solid dosage forms such as tablets, or microencapsulation of live cells.
According to further embodiments of the present invention the particles may also be used for treating inflammation, infection, diabetes, arthritis, and cancer, as well as a method for stimuli-responsive separation of solutes of different sizes in an aqueous medium.
Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.